Identifying distant homologous viral sequences in metagenomes using protein structure information

International audienceIt is estimated that marine viruses daily kill about 20% of the ocean biomass. Identifying them in water samples is thus a biological issue of great importance. The metagenomic approach for virus identication is a challenging task since their sequences carry a lot of mutations making them hardly possible to find by standard homology searches. The PEPS VAG project aims at establishing a novel methodology that uses structures of proteins as extra-information in order to annotate metagenomes without relying on homology of sequences. In the context of the first experiments made on the metagenome of station 23 of the TARA Ocean Project, we use the structures of capsid protein to infer the sequence signature of their fold, in order to find them in the metagenome. We present here the methodology, the first experiments and the on-going improvements

SPROUTS: a database for the evaluation of protein stability upon point mutation

SPROUTS (Structural Prediction for pRotein fOlding UTility System) is a new database that provides access to various structural data sets and integrated functionalities not yet available to the community. The originality of the SPROUTS database is the ability to gain access to a variety of structural analyses at one place and with a strong interaction between them. SPROUTS currently combines data pertaining to 429 structures that capture representative folds and results related to the prediction of critical residues expected to belong to the folding nucleus: the MIR (Most Interacting Residues), the description of the structures in terms of modular fragments: the TEF (Tightened End Fragments), and the calculation at each position of the free energy change gradient upon mutation by one of the 19 amino acids. All database results can be displayed and downloaded in textual files and Excel spreadsheets and visualized on the protein structure. SPROUTS is a unique resource to access as well as visualize state-of-the-art characteristics of protein folding and analyse the effect of point mutations on protein structure. It is available at http://bioinformatics.eas.asu.edu/sprouts.html

Some insights into the transition state ensemble of the folding of globular proteins

International audienceThis issue of Bio-Algorithms and Med-Systems ( BAMS )contains several review papers about some aspects ofthe globular protein folding process. Several modelshave been proposed over the years for the folding, andwe do not intend to give a final answer on this pendingissue. Nevertheless, predictions of some positions alongthe sequence, which are important for the formation ofthe native structure, have reached the point of maturity.These key residues are involved in intra-chain contacts,and even if they are separated in sequence by a so-calledlong range, they constitute the core of the globule aroundwhich the local regular secondary structures take place.The chronology of the formation of these contacts relativeto the secondary structures varies according to the availablemodels

Analyses of displacements resulting from a point mutation in proteins

International audienceThe effects of a single residue substitution on the protein backbone are frequently quite small but there are many other potential sources of structural variation for protein. We present here a methodology considering different sources of distortions in order to isolate the very effect of the mutation. To validate our methodology, we consider a well-studied family with many single mutants: the human lysozyme. Most of the perturbations are expected to be at the very localisation of the mutation, but in many cases the effects are propagated at long range. We show that the distances between the mutated residue and the 5% most disturbed residues, exponentially decreases. One third of the affected residues are in direct contact with the mutated position; the remaining two thirds are potential allosteric effects. We confirm the reliability of the residues assigned as significantly perturbed by comparing our results to experimental studies. We confirm with the present method all the previously identified perturbations. This study shows that mutations have long-range impact on protein backbone that can be detected, although the displacement of the affected atoms is small

PREDICTION DU REPLIEMENT PEPTIDIQUE GRACE AUX INVARIANTS STRUCTURAUX DE PROTEINES HOMOLOGUES

PARIS-BIUSJ-Physique recherche (751052113) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocSudocFranceF

Prédiction des résidus clés du repliement et classification structurale de fragments protéiques en interaction

Nous avons développé un algorithme de prédiction des résidus impliqués dans le noyau du repliement par des approches couplées. La prédiction des Most Interacting Residues (MIR) est associée aux méthodes d analyse structurale par fragments, les Tightened End Fragments (TEF) et d alignement multiple. Cet algorithme a été développé sur une banque de protéines à faible identité en séquence appartenant à une famille bien documentée, les immunoglobulines. Les résultats obtenus sont comparés à ceux produits par d autres techniques similaires, mais aussi à ceux provenant d études expérimentales. Comme résultat nous avons pu voir qu il existe une bonne corrélation entre les résidus prédits par notre méthode et les données expérimentales. Dans une deuxième partie, nous avons généré une banque de multimères biologiques dans le but de développer un outil de prédiction de la structure quaternaire. La banque est validée par le programme DiMoVo utilisant la représentation des protéines par tesselation de Voronoï. Afin d analyser les modes d interaction entre domaines, les différents complexes ont été découpés en fragments par la méthode des Tightened End Fragments. Nous avons développé un algorithme permettant d'inclure chaque fragment dans un cylindre, afin de pouvoir caractériser le fragment par une hauteur et un rayon. Ces fragments ont ensuite été classés sur ces critères structuraux et les interactions de différentes classes de fragments au sein des interfaces protéines-protéines ont été comptabilisées. On observe que les classes ne sont pas utilisées de façon homogène dans les interactions protéines-protéines.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Protein Multiple Alignments: Sequence-based vs Structure-based Programs

International audienceMotivation: Multiple sequence alignment programs have proved to be very useful and have already been evaluated in the literature yet not alignment programs based on structure or both sequence and structure. In the present article we wish to evaluate the added value provided through considering structures.Results: We compared the multiple alignments resulting from 25 programs either based on sequence, structure or both, to reference alignments deposited in five databases (BALIBASE 2 and 3, HOMSTRAD, OXBENCH and SISYPHUS). On the whole, the structure-based methods compute more reliable alignments than the sequence-based ones, and even than the sequence+structure-based programs whatever the databases. Two programs lead, MAMMOTH and MATRAS, nevertheless the performances of MUSTANG, MATT, 3DCOMB, TCOFFEE+TM_ALIGN and TCOFFEE+SAP are better for some alignments. The advantage of structure-based methods increases at low levels of sequence identity, or for residues in regular secondary structures or buried ones. Concerning gap management, sequence-based programs set less gaps than structure-based programs. Concerning the databases, the alignments of the manually built databases are more challenging for the programs

Contribution to the Understanding of Protein–Protein Interface and Ligand Binding Site Based on Hydrophobicity Distribution—Application to Ferredoxin I and II Cases

International audienceFerredoxin I and II are proteins carrying a specific ligand—an iron-sulfur cluster—which allows transport of electrons. These two classes of ferredoxin in their monomeric and dimeric forms are the object of this work. Characteristic of hydrophobic core in both molecules is analyzed via fuzzy oil drop model (FOD) to show the specificity of their structure enabling the binding of a relatively large ligand and formation of the complex. Structures of FdI and FdII are a promising example for the discussion of influence of hydrophobicity on biological activity but also for an explanation how FOD model can be used as an initial stage adviser (or a scoring function) in the search for locations of ligand binding pockets and protein–protein interaction areas. It is shown that observation of peculiarities in the hydrophobicity distribution present in the molecule (in this case—of a ferredoxin) may provide a promising starting location for computer simulations aimed at the prediction of quaternary structure of proteins